An examination of the bidirectional relationship between functioning and symptom levels in patients with anxiety disorders in the CALM study.

BACKGROUND: Patients with anxiety disorders suffer marked functional impairment in their activities of daily living. Many studies have documented that improvements in anxiety symptom severity predict functioning improvements. However, no studies have investigated how improvements in functioning simultaneously predict symptom reduction. We hypothesized that symptom levels at a given time point will predict functioning at the subsequent time point, and simultaneously that functioning at a given time point will predict symptom levels at a subsequent time point. METHOD: Patients were recruited from primary-care centers for the Coordinated Anxiety Learning and Management (CALM) study and were randomized to receive either computer-assisted cognitive-behavioral therapy and/or medication management (ITV) or usual care (UC). A cross-lagged panel design examined the relationship between functional impairment and anxiety and depression symptom severity at baseline, 6-, 12-, and 18-month follow-up assessments. RESULTS: Prospective prediction of functioning from symptoms and symptoms from functioning were both important in modeling these associations. Anxiety and depression predicted functioning as strongly as functioning predicted anxiety and depression. There were some differences in these associations between UC and ITV. Where differences emerged, the UC group was best modeled with prospective paths predicting functioning from symptoms, whereas symptoms and functioning were both important predictors in the ITV group. CONCLUSIONS: Treatment outcome is best captured by measures of functional impairment as well as symptom severity. Implications for treatment are discussed, as well as future directions of research.

Incremental benefits and cost of coordinated anxiety learning and management for anxiety treatment in primary care.

BACKGROUND: Improving the quality of mental health care requires integrating successful research interventions into 'real-world' practice settings. Coordinated Anxiety Learning and Management (CALM) is a treatment-delivery model for anxiety disorders encountered in primary care. CALM offers cognitive behavioral therapy (CBT), medication, or both; non-expert care managers assisting primary care clinicians with adherence promotion and medication optimization; computer-assisted CBT delivery; and outcome monitoring. This study describes incremental benefits, costs and net benefits of CALM versus usual care (UC). METHOD: The CALM randomized, controlled effectiveness trial was conducted in 17 primary care clinics in four US cities from 2006 to 2009. Of 1062 eligible patients, 1004 English- or Spanish-speaking patients aged 18-75 years with panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD) and/or post-traumatic stress disorder (PTSD) with or without major depression were randomized. Anxiety-free days (AFDs), quality-adjusted life years (QALYs) and expenditures for out-patient visits, emergency room (ER) visits, in-patient stays and psychiatric medications were estimated based on blinded telephone assessments at baseline, 6, 12 and 18 months. RESULTS: Over 18 months, CALM participants, on average, experienced 57.1 more AFDs [95% confidence interval (CI) 31-83] and $245 additional medical expenses (95% CI $-733 to $1223). The mean incremental net benefit (INB) of CALM versus UC was positive when an AFD was valued ≥$4. For QALYs based on the Short-Form Health Survey-12 (SF-12) and the EuroQol EQ-5D, the mean INB was positive at ≥$5000. CONCLUSIONS: Compared with UC, CALM provides significant benefits with modest increases in health-care expenditures.

Functioning and disability levels in primary care out-patients with one or more anxiety disorders.

BACKGROUND: Anxiety disorders are the most prevalent mental health disorders and are associated with substantial disability and reduced well-being. It is unknown whether the relative impact of different anxiety disorders is due to the anxiety disorder itself or to the co-occurrence with other anxiety disorders. This study compared the functional impact of combinations of anxiety disorders in primary care out-patients. METHOD: A total of 1004 patients with panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD) or post-traumatic stress disorder (PTSD) provided data on their mental and physical functioning, and disability. Multivariate regressions compared functional levels for patients with different numbers and combinations of disorders. RESULTS: Of the patients, 42% had one anxiety disorder only, 38% two, 16% three and 3% all four. There were few relative differences in functioning among patients with only one anxiety disorder, although those with SAD were most restricted in their work, social and home activities and those with GAD were the least impaired. Functioning levels tended to deteriorate as co-morbidity increased. CONCLUSIONS: Of the four anxiety disorders examined, GAD appears to be the least disabling, although they all have more in common than in distinction when it comes to functional impairment. A focus on unique effects of specific anxiety disorders is inadequate, as it fails to address the more pervasive impairment associated with multiple anxiety disorders, which is the modal presentation in primary care.

Effects of one night's sleep deprivation on mood and behavior in panic disorder. Patients with panic disorder compared with depressed patients and normal controls.

The effects of one night's sleep deprivation on mood and behavior were evaluated in 12 patients with panic disorder, ten depressed patients, and ten controls. In contrast to the improvement in symptoms of anxiety and depression shown by the majority of depressed patients, the response of patients with panic disorder as a group did not differ from that of normal controls, although a subgroup did experience noticeable worsening in their symptoms of anxiety, with 40% experiencing panic attacks on the day following sleep deprivation. Electroencephalographic recordings with nasopharyngeal electrodes on the day following sleep deprivation were normal, further suggesting that patients with panic disorder do not have seizure activity characteristic of temporal lobe epilepsy.

A randomized effectiveness trial of collaborative care for patients with panic disorder in primary care.

BACKGROUND: Effectiveness studies have tested interventions to improve quality of care for depression in primary care, but none, to our knowledge, have been completed for panic disorder (PD) in this setting. This study sought to test the clinical effectiveness of PD pharmacotherapy embedded in a disease management framework of "collaborative care" (CC). METHODS: One hundred fifteen patients with PD from 3 primary care clinics were randomized to CC or "usual care" (UC). Patients in CC (n = 57) received educational videotapes and pamphlets; pharmacotherapy with the selective serotonin reuptake inhibitor paroxetine; 2 psychiatrist visits and 2 telephone calls in the first 8 weeks; and up to 5 telephone calls between 3 and 12 months' follow-up. Usual care patients (n = 58) were treated by their primary care physician. Telephone assessments of panic, anxiety sensitivity, depression, and disability variables were performed at 3, 6, 9, and 12 months' follow-up. Adequacy of pharmacotherapy was assessed with an algorithm based on a review of efficacy studies. RESULTS: Patients in CC were more likely to receive adequate (type, dose, duration) medication and more likely to adhere to this medication at 3 and 6 months. Random regression analyses showed that CC patients improved significantly more over time compared with UC patients on anxiety, depression, and disability measures, with the greatest effects at 3 and 6 months. CONCLUSIONS: Compared with UC, CC interventions significantly improved both quality of care and clinical and functional outcomes in primary care PD patients. Clinical differences were greatest in the first 6 months, corresponding to the greater quality of care and the greater intensity of intervention.

Carbamazepine and thyroid function in affectively ill patients. Clinical and theoretical implications.

Thyroid function was examined in 50 affectively ill patients before and four weeks after carbamazepine treatment. Carbamazepine significantly and substantially decreased peripheral thyroid hormone levels while increases in thyrotropin levels, although significant, were of much smaller magnitude. Furthermore, the decreases in levels of thyroxine (T4) and free T4 were significantly greater in carbamazepine responders than in nonresponders. These findings are discussed in light of current theories of the role of the thyroid axis in affective illness.

Reduced benzodiazepine sensitivity in panic disorder.

We evaluated the functional sensitivity of the gamma-aminobutyric acid-benzodiazepine supramolecular complex in 9 patients with panic disorder and 10 psychiatrically healthy control subjects by comparing the effects of four logarithmically increasing doses of intravenous diazepam on saccadic eye movement velocity, memory, and self-rated sedation. Patients with panic disorder were less sensitive than controls to diazepam using eye velocity as the dependent measure. Sedation and memory effects did not distinguish the two groups. These findings suggest that panic disorder is associated with functional subsensitivity of the gamma-aminobutyric acid-benzodiazepine supramolecular complex in brain-stem areas controlling saccadic eye movements.

Effortful and automatic cognitive processes in depression.

Ten patients with major depression and ten age- and sex-matched normal controls were presented with two contrasting cognitive tasks: one required sustained effort and information processing, and the other required only superficial information processing that could be accomplished automatically, with little effort. Depressed patients performed more poorly only on the effort-demanding cognitive task.

Dysphoric mania. Clinical and biological correlates.

Patients studied at peak severity of a manic episode showed substantial degrees of depression (dysphoria) and anxiety. Compared with nondysphoric manics (n = 26), the dysphoric manics (n = 22) had a significantly greater number of previous hospitalizations, and they displayed less rapid cycling both in the year before and during the index hospitalization admission. The severity of manic dysphoria tended to correlate with the number of previous hospitalizations, a finding that was highly significant in women (n = 27). Medication-free manic patients (n = 22) had significant elevations in cerebrospinal fluid norepinephrine concentrations compared with depressed and euthymic patients and normal volunteers, and the degree of elevation correlated significantly with the degree of manic dysphoria, anger, and anxiety rated at the time of the lumbar puncture. Patients with dysphoric mania, recognized by Kraepelin to have poor prognoses, have been reported to respond poorly to lithium carbonate but may be among those who respond to carbamazepine. Clinical, biologic, and pharmacologic response characteristics of manic subgroups, particularly those with extreme dysphoric components to their illness, appear to be clinically meaningful and deserving of further investigation.

Thyroid function in women with premenstrual syndrome.

UNLABELLED: We have examined the relationship between thyroid function and the presence of symptoms in women with prospectively confirmed premenstrual syndrome (PMS) in the following ways: 1) basal thyroid function tests (n = 124); 2) thyroid auto-antibody levels (n = 63); 3) TRH stimulation tests performed during the follicular phase (n = 39) or during both the follicular and luteal phase (n = 21); and 4) the efficacy of L-T4 in the treatment of PMS (n = 30). RESULTS: Thirteen women (10.5%) had basal evidence of either grade I or II hypothyroidism or hyperthyroidism. Elevated thyroid auto-antibody titers were observed in eight women (13%). Eighteen women (30%) (all with normal basal TSH levels) had abnormal responses to TRH, either blunted (n = 6) or exaggerated (n = 12). L-T4 was not superior to placebo in the treatment of PMS in a double blind placebo controlled cross-over trial. Although it is clear that PMS is not simply masked hypothyroidism, abnormalities of stimulated thyroid function appear with greater than expected frequency in women with PMS and may define a subgroup of women with this disorder. L-T4 supplementation appears to have no place in the routine management of PMS.

Human oculomotor function: reliability and diurnal variation.

To provide information on test-retest reliability for seven oculomotor paradigms currently used in studies of schizophrenia and other neuropsychiatric conditions, we tested eight controls at four weekly intervals, twice in the morning (8-10 AM) and twice in the afternoon (3-5 PM). Intraclass correlation coefficients were significant (p < .05) for both AM and PM pairs of measures as well as for mean AM and PM pairs for closed-loop pursuit gain, open-loop pursuit gain (using velocity as the measure), saccadic frequency during pursuit and fixation, visually and nonvisually guided saccadic latency and velocity, antisaccadic latency, and premature reflexive saccades during the memory-guided saccade task. Acceleration as a measure of open-loop gain (for slower targets) and accuracy of saccades to a moving target were only reliable at PM testing time. Nonvisually guided saccadic accuracy and inappropriate reflexive saccades during the antisaccade task were not reliable, possibly due to the narrow range of values for these measures. Except for approximately 10% fewer saccades during pursuit and fixation in the morning, there were no consistent diurnal differences. These findings suggest that, in a small sample of subjects, most measures of oculomotor function are stable across time and may reflect underlying neurophysiologic traits.

Response to lactate infusion in generalized anxiety disorder.

Intravenous sodium lactate infusion provokes symptoms of panic in patients with panic disorder at a significantly higher rate than in normal controls. Lactate sensitivity has been postulated to be specific for patients with panic attacks regardless of frequency of attacks or coexisting diagnoses. The authors present results of a pilot study of lactate infusions in patients with generalized anxiety disorder (GAD) without any history of panic attacks. Patients with GAD reacted more like panic disorder patients than like normal controls in anxiety and symptom scores during lactate infusion and in the rate of positive responses to lactate. Although preliminary, these findings raise questions regarding the specificity of lactate sensitivity and the relationship of GAD to panic disorder.

Thyroid function and affective illness: a reappraisal.

It has been generally accepted that increased thyroid function facilitates treatment response in depression. Recent data show that response to several antidepressant treatments, particularly lithium and carbamazepine, are associated with decreased thyroid hormone levels. An alternative hypothesis that decreased thyroid indices are related to antidepressant response is proposed and clinical and research implications are discussed.

Platelet [3H]imipramine binding in patients with panic disorder.

[3H]imipramine binding to platelets was measured in 17 drug-free panic disorder patients and 14 healthy controls. No difference in Bmax or Kd values was found between the two groups. Patients with a past history of major melancholic depression or severe agoraphobia had similar binding parameters as panic disorder patients without a history of depression or severe agoraphobia.

Lactate vulnerability after alprazolam versus placebo treatment of panic disorder.

Thirty-six patients with panic disorder underwent sodium lactate infusion before and after 8 weeks of treatment with alprazolam or placebo. With reinfusion, those patients panic-free with chronic alprazolam treatment displayed significantly decreased reactivity to lactate, as measured by subjective symptom ratings, duration of infusion before developing peak lactate-induced symptoms, and the proportion of patients experiencing lactate-induced anxiety or panic. Patients panic-free on placebo, as well as nonresponders to alprazolam treatment, displayed some, although less striking, decreases in reactivity to lactate with reinfusion. As a group, patients clinically unchanged with placebo treatment showed no systematic change in lactate response with reinfusion. Although the small numbers of patients in each treatment outcome group prohibit drawing definitive conclusions, these findings suggest that decreases in lactate-induced panic after successful alprazolam treatment of panic may result from a combination of changes in clinical state and direct effects of the medication.

Neuroendocrine effects of diazepam in panic and generalized anxiety disorders.

The adrenocorticotropic hormone (ACTH), cortisol, and growth hormone responses to four consecutive, logarithmically increasing doses of intravenous diazepam compared with placebo given at 15-min intervals were examined in patients with panic disorder (n = 13), generalized anxiety disorder (n = 8), and healthy controls (n = 13). Diazepam caused dose-dependent decreases in cortisol and increases in GH and dose-independent decreases in ACTH. There were no patient-control differences, possibly due to either the small sample size of the experimental paradigm, which tested subjects in an upright, sitting position in mildly arousing circumstances.

Relationships between neuropsychological and oculomotor measures in schizophrenia patients and normal controls.

Establishing the relationship between oculomotor and neuropsychological impairments might facilitate a more coherent description of schizophrenia-associated neurocognitive deficits. Therefore, we assessed several aspects of neuropsychological and oculomotor function in 25 medicated schizophrenia patients and 24 age-matched controls. Neuropsychological tasks included the Wisconsin Cart Sort Test (WCST), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test, and finger tapping speed. Oculomotor functions assessed included smooth pursuit, initiation of smooth pursuit, predictive pursuit, fixation, visually guided saccades, remembered saccades, and antisaccades. Among the schizophrenia patients, predictive pursuit performance correlated significantly with finger tapping (dominant hand), TMT (both parts), and one WCST measure (categories completed). The only other significant correlation among the schizophrenia patients was between antisaccade performance and part A of the TMT. Perseverative errors during the WCST and antisaccade performance were the only measures significantly correlated among the normals. Closely related neurocognitive deficits may be responsible for impairments in TMT, WCST, predictive pursuit, and antisaccade performance in schizophrenia.

Premenstrual syndromes: overview from a methodologic perspective.

The authors review the available evidence regarding the nature, cause, and treatment of the premenstrual syndromes. They attribute the contradictory results of various studies and the current theoretical confusion in the area to the failure of investigators to carefully define the syndromes, formulate a set of answerable questions, and select a homogeneous population before initiating their studies. The relationship between premenstrual syndromes and major psychiatric disorders, as well as the clinical and theoretical relevance of the menstrual cycle to major psychiatric disorders, is discussed. The authors offer recommendations to both investigators and clinicians for more careful observation and documentation of the relationship between mood disorders and the menstrual cycle.

Graphic representation of the life course of illness in patients with affective disorder.

The authors illustrate methods for the graphic depiction of the course of unipolar and bipolar affective illness. The utility and advantages of such an approach include 1) accurate assessment of episode patterns, 2) elucidation of relationships to environmental events, endocrine and seasonal factors, and psychosocial stressors, 3) better delineation of treatment response, 4) a greater understanding of the longitudinal and characteristic patterns of illness, and 5) the associated better patient management with psychotherapeutic and pharmacological interventions.

Irritable bowel syndrome and psychiatric illness.

Psychiatric illnesses such as mood, anxiety, and somatization disorders share many common features with irritable bowel syndrome. The authors review recent developments in the definition of irritable bowel syndrome and its relationship to psychiatric illness, discuss the diagnostic validity of irritable bowel syndrome from several perspectives, and offer a pathophysiological model of irritable bowel syndrome that integrates many of the biological and psychosocial findings of earlier studies. Psychiatric evaluation appears to be an important factor in the diagnosis and treatment of patients with irritable bowel syndrome.